Thienopyridines are known to have antibacterial activities as well as other activities found recently such as angiotensin II antagonistic activities and GnRH antagonistic activities, due to which they are expected to be used widely in the fields of medicines and agricultural industries. Concerning the synthetic method for 5-acyl-4-hydroxythieno[2,3-b]pyridine derivative, one of such thienopyridines, there are examples reported on a direct synthesis of 5-acetyl-4-hydroxythieno[2,3-b]pyridine from 2-aminothiophene by a method called Gould-Jacobs method characterized by employing an ethoxymethylene compound of an active methylene compound as shown below [M. A. Khan et al., J. Heterocyclic Chem., Vol.14, p. 807 (1977)]: ##STR3##
a synthesis from a corresponding acyl group-containing polysubstituted pyridine as shown below (F. A. Abu-Shanab et al., J. Chem. Soc. Perkin Trans. 1, 1994, page 1449): ##STR4##
and a synthesis through functional group conversion in the 5-position of a 5-ethoxycarbonyl-4-hydroxythieno[2,3-b]pyridine derivative or a 5-cyano-substituted derivative thereof obtained by a conventional procedure as shown below [WO 95/28405 (JP-A-8-295693)]: ##STR5##
whereine R.sup.51 represents hydrogen or a group through a carbon, nitrogen, oxygen or sulfur atom, R.sup.52 represents hydrogen or alkyl, R.sup.53 a hydrocarbon group, and R.sup.54 represents phenylalkylene which may be substituted
In order to produce a thienopyridine derivative having a GnRH antagonistic effect, a compound having a nitrophenyl in the 2-position and a halogenomethyl in the 3-position is produced as an intermediate in WO 95/28405 (JP-A-8-295693). In the production of this compound, a nitro group is first introduced into the phenyl of the compound having a phenyl in the 2-position and a methyl in the 3-position and then the methyl in the 3-position is converted into a halogenomethyl.
Also in WO 95/28405 (JP-A-8-295693), a compound having an acid amide in the 5-position is produced from a compound having a carboxylic acid ester in the 5-position.
In the method by M. A. Khan et al. described above, the product is provided via an undesirable step such as the involvement of an organotin compound in an attempt to avoid the formation of an unstable 2-aminothiophene as an intermediate, while the method by F. A. Abu-Shanab et al. provides a O-ethylated product and involves a limitation in terms of the substituents on the thiophene ring, because of which the range of the application is limited.
On the other hand, the method for obtaining a 5-acyl form by the functionality conversion of a 5-ethoxycarbonyl-4-hydroxythieno[2,3-b]pyridine derivative or a 5-cyano-substituted derivative thereof which are obtained by a conventional method involves a less efficient multiple-stage synthesis. The production of a GnRH antagonistic thienopyridine derivative employing this conventional method disclosed in WO 95/28405 (JP-A-8-295693) involves a large number of the production steps, which also make this method less efficient.
Accordingly, there has still been a desire to develop a method for producing a 5-acyl-4-hydroxythieno[2,3-b]pyridine skeleton conveniently and efficiently.
In the method disclosed in WO 95/28405 (JP-A-8-295693) which involves a conversion of the methyl in the 3-position of a compound having a nitrophenyl in the 2-position and the methyl in the 3-position into a halogenomethyl, carbon tetrachloride is employed as a solvent (see Example 6 in this publication). Since carbon tetrachloride has a high toxicity, an industrial or safety and sanitary consideration encourages to use a method employing no carbon tetrachloride. Nevertheless, no use of carbon tetrachloride results in a disadvantageous intermission of a brominating reaction.
In the method disclosed in WO 95/28405 (JP-A-8-295693), for producing a compound having an acid amide structure in the 5-position from a compound having a carboxylic acid ester in the 5-position, trimethylaluminum is used (see Example 50 in this publication). Since this trimethylaluminum is readily flashing and flammable, highly toxic and should be free from water, it should be handled with a great care. Industrially, a safe production method requiring no use of trimethylaluminum is desired.